AB0564 TIGIT ACTIVATOR ALLEVIATES SYSTEMIC LUPUS ERYTHEMATOSUS BY NEGATIVELY REGULATING TH1-LIKE TREG CELL DIFFERENTIATION
Authors: X. MA, S. Yu, J. Gu, H. Jiang, Y. Shan
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Systemic lupus erythematosus (SLE) is a heterogeneous inflammatory chronic autoimmune disorder characterized by autoimmune tolerance deficiency [1]. T Regulatory cells (Tregs) play an important role in maintaining immune homeostasis. In inflammatory setting, the plasticity of Tregs increased with acquiring effector T helper (Th) phenotype, resulting in the reduction of immunosuppressive ability. It is reported that the frequency of Th1-like Treg cells, which has low suppressive function, increased in autoimmune diseases [2]. T cells Immunoglobulin and TIMI domain (TIGIT) is a co-inhibitory receptor, which can suppress the response of effector T cells. It is identified that the expression of TIGIT on Tregs significantly decreased in SLE [3-4]. Interferon-α (IFN-α) is a crucial pleiotropic cytokine with a high level in SLE and can promote type I immune response. IFN-α depends on AKT/mTOR signaling while phosphorylating JAK/STAT pathway to regulate the polarization of Th1 [5]. <h3>Objectives</h3> The study is to evaluate the characteristics and differentiation mechanisms of Th1-like Treg cells in SLE patients and the role of TIGIT in regulating immunosuppressive function. <h3>Methods</h3> The frequency of Foxp3<sup>+</sup>T-bet<sup>+</sup>Th1-like Tregs of peripheral blood mononuclear cells (PBMCs) from SLE patients and healthy controls were analyzed by flow cytometry. PBMCs and CD4<sup>+</sup>T cells were isolated and cultured under stimulation of IFN-α and/or TIGIT activator. The expression of characteristic markers of Th1-like Tregs, and the activation of AKT/mTOR/STAT pathway were assessed using flow cytometry and PCR. <h3>Results</h3> Th1-like Tregs with low TIGIT expression expanded in SLE patients. IFN-α promoted the conversation of Tregs to Th1-like Tregs through phosphorylated STAT4. TIGIT reactivation reversed the polarization of Th1-like Tregs and plasmablast differentiation induced by IFN-α through AKT/mTOR/STAT4 pathway. <h3>Conclusion</h3> Our findings indicate that the expansion of Th1-like Tregs and the decreased expression of TIGIT may contribute to the tolerance deficiency in SLE. TIGIT can reverse IFN-α-induced Th1-like Tregs and the impairment of immunosuppressive function, which is a potential therapeutic target for SLE. <h3>References</h3> [1]Pan L, Lu MP, Wang JH, Xu M, Yang SR. Immunological pathogenesis and treatment of systemic lupus erythematosus. World J Pediatr. 2020. 16(1): 19-30. [2]Kitz A, Dominguez-Villar M. Molecular mechanisms underlying Th1-like Treg generation and function. Cell Mol Life Sci. 2017. 74(22): 4059-4075. [3]Lucca LE, Axisa PP, Singer ER, Nolan NM, Dominguez-Villar M, Hafler DA. TIGIT signaling restores suppressor function of Th1 Tregs. JCI Insight. 2019. 4(3). [4]Mao L, Hou H, Wu S, et al. TIGIT signalling pathway negatively regulates CD4(+) T-cell responses in systemic lupus erythematosus. Immunology. 2017. 151(3): 280-290. [5]Matsumoto A, Ichikawa T, Nakao K, et al. Interferon-alpha-induced mTOR activation is an anti-hepatitis C virus signal via the phosphatidylinositol 3-kinase-Akt-independent pathway. J Gastroenterol. 2009. 44(8): 856-63. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.